A Case Series of New-Onset Ulcerative Colitis Following Recent Diagnosis of COVID-19

There have been only 2 reported cases of new-onset ulcerative colitis in pediatrics following acute coronavirus disease 2019 (COVID-19). We are reporting a case series of 3 adolescent female patients, 2 of whom were vaccinated against COVID-19, who developed new-onset ulcerative colitis following a recent diagnosis of COVID-19 infections at a singular pediatric hospital. This case series should be an impetus to clinicians who have pediatric patients with persistent symptoms of hematochezia, diarrhea, and abdominal pain following acute COVID-19 infection to consider further workup for inflammatory bowel disease.


INTRODUCTION
This is the third reported case series of 3 pediatric patients with new-onset ulcerative colitis (UC) following acute coronavirus disease 2019 (COVID-19).There have been 2 cases involving a 9-year-old female and a 13-year-old female who developed UC following COVID-19 (1,2).There have been a small number of cases of new-onset inflammatory bowel disease (IBD) following acute COVID-19 in adults including a previously healthy, fully-vaccinated 21-year-old male (3).

CASES
The cases are summarized in Table 1.

DISCUSSION
An infectious trigger of IBD has been previously described in intestinal infections such as Cytomegalovirus, Mycobacterium avium subspecies paratuberculosis, adherent-invasive Escherichia coli, and Campylobacter species (4).The SARS-CoV-2 virus can presumably trigger IBD via 2 different intracellular pathways, the endosomal pathway and the membrane (cytoplasmic) pathway.This mechanism, as described in Dvornikova et al. (5), is summarized below.In the endosomal pathway, the SARS-CoV-2 S glycoprotein attaches to intestinal enterocytes via the ACE2 receptor that is highly expressed in intestinal enterocytes.The virus is ferried to the endosome.In the endosome, the viral RNA activates the TRIF and the MyD88-dependent pathway pathways, respectively.The activation of the TRIF pathway eventually leads to the induction of IRF3 which produces IFN-α,β.The MyD88 pathway leads to the production of cytokines such as IL-1, IL-6, and TNF-α.Another membrane receptor, TLR4 also attaches to the SARS-CoV-2 S glycoprotein.TLR4 also induces IRF3.The SARS-CoV-2 Viroporin 3a protein via IL-1β and the recognition of viral RNA and proteins leads to the assembly of the NLRP3-inflammasome that has been implicated in worsening colonic mucosal lesions in patients with IBD.The adaptive immune response also plays a role in which the macrophages and dendritic cells display the SARS-CoV-2 virus to T-cells that differentiate into Th1 and Th17 cells.Th1 and Th17 cells then produce a cytokine storm, as described in Wu et al. (6), that decreases the SARS-CoV-2 load but precipitates the development of IBD.
Our case series suggests that COVID-19 vaccination does not prevent the development of UC, but larger sample sizes would be needed.It is also notable that all 3 patients were responsive to infliximab, which may further investigation and may lead to insights into how the virus can trigger IBD.There are only a few reported cases of adult patients who developed IBD following COVID-19 and 2 case reports of pediatric patients who developed new-onset Crohn disease, including 1 with concurrent multi-inflammatory syndrome in children (7).Finally, this case series confirms epidemiological assessments of IBD in New York City that have suggested a link between COVID-19 and UC (8).

CONCLUSION
In a genetically predisposed individual, any viral infection can trigger the onset of IBD.There are some unique pathogenetic pathways that could trigger the onset of IBD after COVID-19 infection and it is important to note that in this small case series, the vaccination did not prevent the dysregulation of immune pathways resulting in IBD.However, larger studies are needed to determine if the risk of developing IBD is higher with COVID-19 as compared to other infections.We hope to impress upon our clinical colleagues the importance of considering new-onset IBD in patients with persistent hematochezia, diarrhea, and abdominal pain following acute COVID-19.

TABLE 1. A summary of the 3 patients included in the case series
the presentation COVID-19 course No hospitalizations or use of antiviral treatments No hospitalizations or use of antiviral treatments No hospitalizations or use of antiviral treatments Presenting symptoms 3 weeks of abdominal pain and hematochezia 1 month of abdominal pain, hematochezia, headaches, nausea and fatigue Abdominal pain and hematochezia Family history Crohn disease in her paternal aunt and paternal second cousin No family history of IBD or autoimmune disorders No family history of IBD or autoimmune characterized by adherent blood, altered vascularity, edema, erosions, erythema, and confluent ulcerations was found throughout the colon Inflammation in a continuous and circumferential pattern from the anus Infectious stool studies include Salmonella, Shigella, Campylobacter, E. coli 0157:H7, Shiga Toxin 1 and 2, Yersinia, C. difficile, Giardia species and Cryptosporidium. *